This new NIEHS Center for Neurodegeneration Science (CMS) application will study the effect of environmental toxins on Parkinson's disease (PD). The Grant is based at the Burnham Institute for Medical Research (BIMR), The Scripps Research Institute (TSRI), and the University of California at San Diego (UCSD), all within a mile of each other in La Jolla, California. This group of neuroscientists has a strong history of working together in PD-related projects. BIMR and TSRI represent two of six NIHdesignated Roadmap Chemical Screening Centers. We will leverage these chemical-screening centers in this proposal to look for new drugs to treat PD. The Center is comprised of four Projects and four Scientific Cores (plus an Administrative/ BioStatistical Core and a Research Development Core) to support these projects. The Overall Theme of the Projects concerns how S-nitrosylation (SNO adduct formation) and further oxidation can mimic genetic mutations involved in PD to cause protein misfolding, abnormal signaling, and eventually neuronal cell injury and death. Our final goal will be to generate novel hits from chemical library screens to offset this damage. Human material will be assessed for new SNO-Biomarkers and correlated to disease state, representing a human clinical component as defined in the RFA. The projects describe a novel complex of parkin/PINK1/DJ-1 and how this complex influences parkin E3 ligase activity and neuronal cell death (Project 1). The projects then proceed to study the deleterious effects of oxidative/nitrosative stress on this complex and other PD-related molecules that affect protein misfolding (Projects 2 and 3). From this information, novel therapies are sought by high-throughput screening (HTS) of chemical libraries using platforms of lower organisms (drosophila-based screens of Project 2) and in recombinant protein and cell-based screens (Project 3). After medicinal chemistry optimization, these novel hits are then further tested in human embryonic stem cell (hESC)-derived dopaminergic neurons (Project 4). This project will also study developmental vulnerability to PD-related abnormal proteins or oxidative/nitrosative stress as cells develop into dopaminergic neurons derived from hESCs. Taken together, this Center offers a comprehensive study of the effects of environmental stress (represented by oxidation and S-nitrosylation) on PD-related proteins, and will develop new therapeutics based on this novel approach.